Pharmacokinetics of ethambutol and weight banded dosing in South African adults newly diagnosed with tuberculosis and HIV

Resumo original em inglês

O que aconteceu

Ethambutol is used to treat tuberculosis (TB) in individuals living with HIV. Low concentrations of ethambutol have been reported in patients dosed with the World Health Organization (WHO)-recommended first-line regimen. We analyzed the pharmacokinetics of ethambutol in 61 HIV-positive individuals diagnosed with drug-sensitive TB enrolled in the tuberculosis and highly active antiretroviral therapy (TB-HAART) study. Participants started on TB treatment and were randomized to early or later introduction of efavirenz-based antiretroviral treatment. We explored potential covariate effects and evaluated the current WHO dosing recommendations for ethambutol in drug-susceptible and multidrug-resistant (MDR)-TB. A two-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption best described the pharmacokinetics of ethambutol. Clearance was estimated to be 40.3 L/h for a typical individual with a fat-free mass (FFM) of 42 kg. The Antib-4 formulation had 26% higher bioavailability and slower mean transit time by 37% compared with Rifafour. Simulations showed that individuals in the lower weight bands (<55 kg) who were administered ethambutol at WHO-recommended doses had relatively low drug exposures. These individuals would need doses of 825 mg if their body weight is <37.9 kg and 1,100 mg if it is between 38 and 54.9 kg to achieve the reference maximum concentrations of 2-6 mg/L and an area under the concentration-time curve (0-24) of 16-29 mg·h/L. To achieve these targets in MDR-TB treatment, a dose increment of 400 mg (extra tablet) would be required for individuals in the lower weight band (<46 kg). Our dose adjustments are consistent with the literature and can be recommended for consideration by the WHO for first-line drug-susceptible and MDR-TB treatment.

Resumo publicado sob licença CC BY. A tradução para o português ainda não chegou a este estudo.